Influence of dopamine-related genes on craving, impulsivity, and aggressiveness in Korean males with alcohol use disorder.

Dopamine is a major neuromodulator that is acutely involved in various cognitive processes, reward-motivated behaviors, and impulsivity. Abnormality in dopaminergic neurotransmission is implicated in the pathophysiology of alcohol use disorder (AUD). The present study examined the genetic influence of dopamine system on problematic drinking, impulsivity, and aggressiveness in a Korean male population with AUD. Five single nucleotide polymorphisms (SNPs) (rs4532 in DRD1, rs2283265 in DRD2, rs6280 in DRD3, rs1800497 in ANKK1, and rs4680 in COMT) and a variable number of tandem repeats (VNTRs) in DAT1 in 295 male patients with AUD were genotyped. For AUD-related clinical characteristics, the Alcohol Use Disorders Identification Test and the Obsessive-Compulsive Drinking Scale (OCDS) were used to assess the severity of hazardous drinking and craving symptoms, respectively. Participants also completed the UPPS-P Impulsive Behavior Scale (UPPS-P) and Buss-Perry Aggression Questionnaire (BPAQ). Analyses were performed using R package SNPassoc; statistical significance was set as p < 0.0083 after Bonferroni correction. A significant association was detected between DRD3 SNP rs6280 and OCDS scores. In regard to impulsivity and aggressiveness, rs4532 of DRD1 was significantly associated with UPPS-P score. Also, rs4532 demonstrated a nominally significant association with BPAQ score, although it did not reach statistical significance after correction for multiple comparisons. Results of this study support the idea that genetic variations in the dopamine system may contribute to alcohol cravings and impulsivity in patients with AUD.

Serial mediating effects of childhood trauma and conduct behaviors on the impact of family history among patients with alcohol use disorder.

Family history (FH) of alcoholism increases the risk of alcohol use disorder (AUD); however, the contribution of childhood trauma (CT) in this respect remains unclear. This study investigated the relationship between FH and AUD-related clinical characteristics (social onset, antisocial tendency, and severity of problematic alcohol consumption) through the mediating effects of childhood trauma (CT) and conduct behaviors (CB) in a Korean male population with AUD. A total of 304 patients hospitalized for AUD at 16 psychiatric hospitals completed standardized questionnaires, including self-rated scales. Mediation analyses were performed using the SPSS macro PROCESS. Individuals with positive FH (133, 44%) had greater CT and CB and more severe AUD-related clinical characteristics than those without FH (171, 56%). In the present serial mediation model, FH had significant direct and indirect effects on AUD-related clinical characteristics through CT and CB. Indirect effects were 21.3% for social onset, 46.3%, antisocial tendency, and 37.9% for problematic drinking. FH directly contributed to AUD-related clinical characteristics, and CT and CB played mediating roles. This highlights the importance of careful intervention and surveillance of adverse childhood experiences and conduct disorder to prevent and mitigate alcohol-related problems in individuals with FH of AUD.

Genetic association of FKBP5 with trait resilience in Korean male patients with alcohol use disorder.

The FKBP5 gene is known to have an important role in alcohol use disorder (AUD) in response to stress and has been reported to affect stress responses by interacting with childhood trauma. This study investigated the effects of the FKBP5 polymorphism rs1360780 and childhood trauma on trait resilience in male patients with AUD. In addition, allele-specific associations between FKBP5 DNA methylation and resilience were examined. In total, 297 men with AUD were assessed for alcohol use severity, childhood trauma, resilience, and impulsivity. Genotyping for FKBP5 rs1360780 and DNA methylation were analyzed. The effects of the rs1360780 single nucleotide polymorphism (SNP) and clinical variables on resilience were tested using linear regression analysis. Possible associations between FKBP5 DNA methylation and resilience were tested with partial correlation analysis. The rs1360780 risk allele, a low education level, and high impulsivity were associated with diminished resilience, whereas no significant main or interaction effect of childhood trauma with the SNP rs1360780 genotype on resilience was shown. No significant association between FKBP5 DNA methylation and resilience was found. The present study demonstrated the involvement of the rs1360780 risk allele in trait resilience in men with AUD, suggesting that the genetic vulnerability of FKBP5 may influence resilience related to AUD.

Association of PPM1G methylation with risk-taking in alcohol use disorder.

Alcohol use disorder (AUD) is a chronic and relapsing disease with a substantial genetic influence. Given the recent discovery of the association of PPM1G methylation with alcohol use disorder (AUD) from a genome-wide methylation study, we sought to verify and extend the previous work of AUD-related impulsivity in a Korean population with AUD. A total of 244 men with AUD were assessed for psychological characteristics and behavioral impulsivity using stop signal task (response inhibition) and Balloon Analog Risk Task (risk-taking). Leukocyte DNA methylation at PPM1G was quantified using pyrosequencing. The effects of PPM1G methylation on severity of problematic drinking measured by Alcohol Use Disorder Identification Test (AUDIT) and multidimensional impulsivity were tested using linear regression analyses. Hypermethylation of PPM1G was significantly associated with risk-taking propensity among men with AUD. No significant association of PPM1G methylation was found to be associated with AUDIT scores and response inhibition. Our findings indicate that altered methylation of PPM1G may influence the impulsive choice of risk-taking in AUD. Further research is required in order to determine the role of PPM1G in the pathophysiology of AUD and multidimensional impulsivity.

Publisher Correction: Association of PPM1G methylation with risk-taking in alcohol use disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Association of opioid receptor gene polymorphisms with drinking severity and impulsivity related to alcohol use disorder in a Korean population.

AIMS: Recent evidence suggests that the opioid system is implicated in the pathophysiology of alcohol use disorder (AUD). We aimed to examine the genetic influence of opioid receptors on susceptibility to AUD and its clinical and psychological characteristics including harmful drinking behavior and various aspects of impulsivity in AUD patients. METHODS: Three µ-opioid receptor gene (OPRM1) variants and two κ-opioid receptor gene (OPRK1) variants were examined in 314 male patients with AUD and 324 male controls. We applied the Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS), and Alcohol Dependence Scale. AUD patients also completed the stop-signal task, delay discounting task, balloon analogue risk task, and the Barratt Impulsiveness Scale version 11 (BIS-11). RESULTS: No significant differences in genotype distributions or haplotype frequencies were found between AUD patients and controls. However, OPRK1 SNP rs6473797 was significantly related to the severity of alcohol-related symptoms as measured by AUDIT and OCDS and a haplotype containing rs6473797 was also related to OCDS scores in AUD patients. For other psychological traits, OPRM1 SNP rs495491 was significantly associated with scores on the motor subfactor of the BIS-11. CONCLUSION: Genetic variations in opioid receptors may contribute to symptom severity and impulsivity in AUD patients.

Multidimensional impulsivity as a mediator of early life stress and alcohol dependence.

Early life stress (ELS) leads to increased susceptibility to serious psychiatric problems such as alcohol dependence, but the mechanisms through which ELS affects alcohol dependence are unclear. We investigated the mediating role of multi-dimensional impulsivity in the associations between ELS and alcohol dependence. 330 male patients with alcohol dependence (mean age = 48.39) completed self-rating scales of ELS and several self-report measures of impulsivity as well as balloon analogue risk task (BART). After classifying different dimensions of impulsivity using factor analysis, structural equation modeling was conducted to test the mediation effects of impulsivity between ELS and alcohol dependence severity and social onset of hazardous drinking. Among the participants, 64.8%, 42.1% and 47.9% reported at least one episode of childhood maltreatment, sexual abuse and parental conflict, respectively. Response impulsivity-sensation seeking, reflection impulsivity and aggression partially mediated the association between ELS and severity of alcohol dependence (CFI = 0.902 and RMSEA = 0.079). Reflection impulsivity dimension partially mediated the association between ELS and social onset of hazardous drinking (CFI = 0.939, RMSEA = 0.091). These finding imply that stabilizing vulnerabilities such as reflection impulsivity via intervention programs that target young individuals with ELS may be helpful in delaying the onset of hazardous drinking and prevent alcohol dependence.

Telomere length in alcohol dependence: A role for impulsive choice and childhood maltreatment.

Telomere shortening, a marker of cellular aging, has been considered to be linked with psychosocial stress as well as with chronic alcohol consumption, possibly mediated by oxidative stress and inflammatory response. Recent findings suggested that early life adversity on telomere dynamics may be related to impulsive choice. To further our understanding of the association of impulsive choice and childhood trauma on telomere length, we examined whether delayed discounting and childhood trauma or their interaction is related to leukocyte telomere length, while controlling for multiple potential confounding variables, in patients with alcohol dependence who are considered to have higher impulsive choice and shorter telomere length. We recruited 253 male patients with chronic alcohol dependence. All participants performed the delay discounting task, and the area under curve was used as a measure of delay discounting. Steeper delay discounting represents more impulsive choices. The modified Parent-Child Conflict Tactics Scale was used to measure childhood maltreatment. In addition, confounding factors, including socio-demographic characteristics, the Alcohol Use Disorders Identification Test, the Buss-Perry Aggression Questionnaire, the Resilience Quotient, the Beck Depression Inventory, and the Beck Anxiety Inventory, were also assessed. Hierarchical regression analyses showed a significant main effect of delay discounting (ß=0.161, t=2.640, p=0.009), and an interaction effect between delay discounting and childhood maltreatment on leukocyte telomere length (ß=0.173, t=2.138, p=0.034). In subsequent analyses stratified by childhood maltreatment, patients with alcohol dependence and high childhood trauma showed a significant relationship between delay discounting and leukocyte telomere length (ß=0.279, t=3.183, p=0.002), while those with low trauma showed no association between them. Our findings suggest that higher impulsive choice is associated with shorter telomere length, and childhood trauma may exert a moderating effect in the relationship between impulsive choice and telomere length.